Acetoxymethyl acetamides and acetamidoacetamides and their preparation

ABSTRACT

A PROCESS IS DISCLOSED IN WHICH AN N((4-OXO-4H-3,1BENZONXAZIN-2-YL) ACYLOXYMETHYL) LOWER FATTY ACID AMIDE IS PREPARED BY A REACTION OF AN ACID ANHYDRIDE WITH A SUBSTITUTED AMINOACETYL ANTHRANILIC ACID. THE REACTION PRODUCT IS THEN TREATED WITH A COMPOUND POSSESING AN ACTIVE HYDROGEN AND A NUCLEOPHILIC GROUP, I.E. AND AMINE, WHEREBY THERE IS FORMED A 2-CARBAMYL-ACETANILIDE IN WHICH ONE NUCLEOPHILIC GROUP ATTACHES TO THE METHYLENE RADICAL OF THE ACETYL GROUP AND ANOTHER TO THE CARBONYL GROUP OF THE ACETANILIDE. THE COMPOUNDS OF THE INVENTION ARE CENTRAL NERVOUS SYSTEM DEPRESSANTS, RESULTING IN A GENERALLY RELAXING OR SEDATIVE EFFECT.

United States Patent ACETOXYMETHYL ACETAMIDES AND ACETAMI- DOACETAMIDES AND THEIR PREPARATION Stanley C. Bell, Montgomery, Ronald .I. McCaully, Chester, and Scott J. Childress, Philadelphia, Pa., assignors to American Home Products Corporation, New York,

No Drawing. Continuation-impart of applications Ser. No.

456,533, May 17, 1965, and Ser. No. 677,029, Oct. 23, 1967. This application June 8, 1970, Ser. No. 44,547 Int. Cl. C07c 103/44 US. Cl. 260562 N 1 Claim ABSTRACT OF THE DISCLOSURE A process is disclosed in which an N[(4-oxo-4H-3,lbenzoxazin-2-yl)acyloxymethyl] lower fatty acid amide is prepared by a reaction of an acid anhydride with a substituted aminoacetyl anthranilic acid. The reaction product is then treated with a compound possessing an active hydrogen and a nucleophilic group, i.e., an amine, whereby there is formed a 2-carbamyl-acetanilide in which one nucleophilic group attaches to the methylene radical of the acetyl group .and another to the carbonyl group of the acetanilide. The compounds of the invention are central nervous system depressants, resulting in a generally relaxing or sedative effect.

This application is a continuation-in-part of application Ser. No. 456,533, filed May 17, 1965, which issued on May 7, 1968 as US. Pat. 3,382,243 and of application 677,029 filed Oct. 23, 1967 and now US. Pat. 3,534,031.

This invention relates to novel substituted 2-acylamino acetamides, the intermediates for preparing them, and particularly the process for the manufacture and the use thereof.

The process of the invention involves the concept of treating an N-hydroxyarnino or N-acyloxy-N-acyl-amino acetyl anthranilic acid with a lower fatty acid anhydride, for example, acetic anhydride, that forms an N[(4-oxo- 4H-3,1-benzoxazin-2-y1)acetoxymethyl] acetamide. The latter is treated with a compound possessing at least one reactive hydrogen atom combined with a nucleophilic group whereby the latter, surprisingly causes ring rupture to form a Z-carbamyl-acetanilide by attaching as a substituent to the alpha carbon of the acetyl nucleus, and also attaches to the Z-carbonyl group on the benzene ring.

One method for preparing the novel acetamides and intermediates may be illustrated in the following specific sequence of reaction steps:

NHZOH NHCOCHgNHOH Cl C 0 OH O 0 OH IV V JI(R CO) O (2) N N BH CCI HNHOR O OOR Base Cl C I VIII ice

NH-( J(IJHNHHIR Cl C OB In the above series of reactions, the starting material is prepared by reacting anthranilic acid with chloracetyl chloride under known conditions, forming the expected chloroacetamide. The chlorine is then displaced with iodine, also under known conditions, to form the corresponding iodoacetamide shown as Compound IV.

The isolated iodoacetamide is now reacted as (1) to form a hydroxyamino acetamide (Compound V). This is carried out under carefully controlled reaction conditions utilizing hydroxylamine, preferably as the hydrochloride or sulfuric acid salt, in an alcoholic solvent, preferably ethanol. The reaction media must have sufficient basicity to yield free hydroxylamine and, therefore, enough base is added to give a stoichiometric excess of hydroxylamine. A pH from about neutrality to pH 9 will permit the reaction to proceed satisfactorily. A reaction temperature from about 50 to 100 C., preferably from about to C. has been found effective.

The hydroxyarninoacetyl anthranilic acid is treated (Reaction 2) with a lower fatty acid anhydride, represented as (R CO) O in which R represents a lower alkyl, preferably methyl, under relatively mild conditions at about 50 C. to C. but preferably steam bath temperature to form the benzoxazine, an N-[(4-oxo-4H-3,l-benzoxazine-2-yl)acyloxymethyHlower fatty acid amide, represented as Compound VIII.

The novel benzoxazine is then reacted with a compound having an active hydrogen and a nucleophilic group as previously mentioned, which is represented as BH, the symbol B standing for a nucleophilic group such as an amino, a substituted amino, a morpholino, a lactam anion, a sulfonarnide anion, a substituted oxy or a substituted mercapto group. Thus, the nucleophilic reactant represented as BH, is preferably intended to cover ammonia; a monoor di-substituted amine, the substitutent or substituents being lower alkyl or aralkyl radicals; or morpholine.

The final Reaction (3) is carried out by reacting the acyloxyacylamino compound with a solution of the nucleophilic reactant, the desired reaction taking place at a temperature within 0 to C., and preferabl within the range of 20 to 80 C. Solvents useful in the reaction may be the lower aliphatic alcohols, the lower alkyl ethers, diethyl ether, dioxane or other inert solvents in which the reactants are soluble. The reaction should take place under basic conditions, which may be realized by the characteristics of the nucleophilic reagent itself. Where the latter is weakly basic or is essentially unreactive as a base, as in the case of a lower alkanol, it is necessary to add a strongly basic material, for example, sodium hydroxide to cause the reaction to proceed in the desired direction. An amount of base in excess of the stoichiometric amount is desirable.

The bicyclic Compound VIII may be made by another route which is illustrated specifically as follows:

Cl- O VII g In the latter reaction sequence, where R has the meaning previously indicated, Compound VII may first be prepared by reacting hydroxyaminoacetic acid with a selected lower fatty acid anhydride for the initial acylation reaction, after which one adds thionyl chloride. The minimum amount of anhydride necessary for complete reaction is used and the reaction is carried out at a temperature ranging from about to 80 C. The temperature of reaction has been found to be critical and a temperature of about 60 to 70 C. will result in optimum yields. In place of the acid anhydride, one may use an acyl halide. Also, in place of thionyl chloride, which is preferred, one may use phosphorus pentachloride, or bromide.

The amination reaction with the halogenated anthranilic acid, identified as Reaction (4), is carried out at approximately room temperature, or, if necessary, at a temperature up to the refluxing temperature of the reaction mixture. This reaction replaces the reactive chlorine atom with the selected group of the anthranilic acid to form the desired acetamide represented as Compound IX.

In Reaction (5) the use of an acid anhydride or its equivalent also causes ring closure with the elimination of the acyloxy group and the attachment of an acyloxy group acting as a nucleophile to the methylene carbon. The reaction is carried out essentially as in the case of Reaction (2) preferably heating Compound IX with the acid anhydride on a steam bath, which results in the aforesaid benzoxazine, represented as Compound VIII.

The novel acetamides obtained in the final reactions with the nucleophilic compound, represented by Formula I, are pharmacologically active and deemed useful as central nervous system depressants, resulting in a generally relaxing or sedative effect. This was demonstrated by tests with mammals (mice) carried out by acceptable pharmacological procedures. In such procedures, standard graduated doses are used, normally up to 400 mg./kg. In this present case clearly observable decreased motor activity was noted in the neighborhood of about 100 mg./ kg. when the test compound was injected parenterally (IP).

The above mentioned final compounds may be characterized as generally white solids having relatively high melting points and crystallizable out of ethyl alcohol. They are substantially water-insoluble but soluble in the common polar solvents. When acid-addition salts can be formed, the latter are then water-soluble to a material degree. The structural configuration of the compounds was determined by the reactants used and confirmed by known measurement procedures including infra-red analysis and determination of the nuclear magnetic resonance spectrum.

The following examples illustrate the various features of the invention in greater detail. Temperatures as given are to be understood as being in degrees centigrade.

4 EXAMPLE 1 2-iodoacetamido-S-chlorobenzoic acid, M.P. l86-188 is prepared from 2-chloroacetamido-5-chlorobenzoic acid and a molar excess of sodium iodide in 200 ml. of acetone, refluxed for 3 hours, cooled and diluted with water. The resultant precipitate was recrystallized from ethanol.

Analysis.-Calcd. for C H CIINO (percent): N, 4.12; Cl, 10.44; I, 37.38. Found (percent): N, 4.38; CI, 10.40; I, 37.4.

EXAMPLE 2 2-chloroacetamido-5-chlorobenzoic acid was prepared from 40 g. of S-chloroanthranilic acid and 34 g. of chloroacetylchloride and the product, M.P. 214-217", was recrystallized from a water-alcohol mixture.

AnaZysis.-Calcd. for C H C1 NO (percent): C, 43.56; H, 2.84; N, 5.64; CI, 28.58. Found (percent): C, 44.02; H, 3.08; N, 5.59; Cl, 28.40.

EXAMPLE 3 S-chloro-N-(hydroxyaminoacetyl) anthranilic acid. To a solution of 136 g. of 2-iodoacetamido-5-chlorobenzoic acid in 800 ml. of ethanol, warmed to 75, was added a solution of 88 g. of hydroxylarnine hydrochloride in 400 cc. of 4 N sodium hydroxide solution. The solution was heated at for 10 min., chilled, and diluted with 1 l. of Water to obtain the title product.

Analysis.Calcd. for C H ClN O (percent): C, 44.3; H, 3.7; CI, 14.5. Found (percent): C, 44.58; H, 3.78; Cl, 14.35.

EXAMPLE 4 N ([acetyl(acetoxy) amino]acetyl)-5-chloroanthranilic acid. A mixture of 2.0 g. of hydroxyaminoacetic acid was heated in 30 ml. of acetic anhydride with stirring for 20 min. at 60. The excess acetic anhydride was removed in 'vacuo and the residue dissolved in 20 ml. of methylene chloride and 6 ml. of thionyl chloride and refluxed for 5 min. The solvent was removed in vacuo and the residue was dissolved in 30 ml. of methylene chloride and added to 7 g. of 5-chloro-anthranilic acid in 60 ml. of 1,2-dimethoxyethane. The insoluble hydrochloride salt of the starting amine was filtered from the reaction mixture. The filtrate was concentrated to dryness and the residue recrystallized from ethanol giving the product, M.P. 182- 183.

Analysis.Calcd. for C H ClN O (percent): C, 47.50; H, 3.98; N, 8.52; CI, 10.78. Found (percent): C, 47.72; H, 4.13; N, 8.37; CI, 10.7.

EXAMPLE 5 N ([acetyl(acetoxy)amino]acetyl) anthranilic acid, methyl ester, M.P. 94-96", is prepared from methyl anthranilate, hydroxyaminoacetic acid and acetic anhydride according to the procedure of Example 4.

Analysis.Calcd. for C H N O (percent): C, 54.54; H, 5.23; N, 9.09. Found (percent): C, 54.69; H, 5.18; N, 8.96.

EXAMPLE 6- N [6-chloro-4-oxo-4H-3,l-benzoxazin 2 yl)acetoxy methyllacetamide. A solution of 3.6 g. of 5-chloro-2-hydroxyaminoacetylanthranilic acid and 50 m1. of acetic anhydride Was heated for 1 hour on the steam bath and partially concentrated. White crystals, 2.1 g. M.P. 208- 210 dec., were obtained on cooling.

Analysis.-Calcd. for C H ClN O (percent): C, 50.25; H, 3.56; N, 9.02; Cl, 11.41. Found (percent): C, 50.32; H, 3.52; N, 8.85; Cl, 11.40.

EXAMPLE 7 2-acetamido-4-chloro-2-(methylamino) 2 methylcarbamoylacetanilide, M.P. 186189. A mixture of N[(6 chloro-4-oxo-4H-3,l-benzoxazine 2 yl) acetoxy methyl] acetamide in ethanol was added dropwise to a solution of methylamine reactant in absolute ethanol. The solution was heated at 70 C. for one hour. The solvent and excess reactant were removed and the residue was crystallized from ethanol-water.

Analysis.Calcd. for C H C1N O (percent); C, 49.91; H, 5.49; N, 17.91; Cl, 11.34. Found (percent): C, 49.76; H, 5.08; N, 18.34; CI, 11.5.

What is claimed is:

1. The compound, 2-acetamido-4'-chloro-2-(methylamino) -2'- methylcarbamoyl) acetanilide.

References Cited UNITED STATES PATENTS 3,344,136 9/1967 Bell et a1 260-562 5 HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R.

l0 260--244 R, 247.2 A, 500.5 H, 518 A, 544 Y, 545 R;

PC4050 UNITED STATES PATENT OFFICE 69 (IERTIFIQATE OF CQRRECTION Patent No. 3, 631, 105 Dated Decemb-ef L8 1371 Scott J. Inventor(s) Stanley C. Bell, Ronald J. McCaully and Childress It is certified that error appears in the. above-identified patent and that said Letters Patent are hereby porrected as shown below:

f At column 1 in formula V, Cl is omitted. Formula V should i be es follows:

use OCHZNHOH (SEAL) Attest:

EDNARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

